title: Proteomic signature of fatty acid biosynthesis inhibition available for in vivo mechanism-of-action studies.
abstract: Fatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition in Bacillus subtilis using platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess the in vivo mechanisms of action of compounds derived from structure-activity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature in B. subtilis consisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs.
authors.affiliation: Ruhr-Universität Bochum, Mikrobielle Antibiotikaforschung, Biologie der Mikroorganismen, Universitätsstraße 150, Bochum 44801, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wenzel
authors.forename: Malay
authors.initials: M
authors.lastname: Patra
authors.forename: Dirk
authors.initials: D
authors.lastname: Albrecht
authors.forename: David Y-K
authors.initials: DY
authors.lastname: Chen
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
authors.forename: Julia E
authors.initials: JE
authors.lastname: Bandow
mesh_terms: D000218:Adamantane / Q000494:pharmacology*; D062365:Aminobenzoates / Q000494:pharmacology*; D000627:Aminophenols / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000378:metabolism; D001426:Bacterial Proteins / Q000096:biosynthesis*; D055808:Drug Discovery; D005227:Fatty Acids / Q000096:biosynthesis*; D011083:Polycyclic Compounds / Q000494:pharmacology*; D040901:Proteomics
chemical_list: D062365:Aminobenzoates; D000627:Aminophenols; D000813:Anilides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005227:Fatty Acids; D011083:Polycyclic Compounds; D000218:Adamantane; C510909:platensimycin; C520340:platencin